NCT00069784|CompletedPhase 3ResultsDMC

The ORIGIN Trial (Outcome Reduction With Initial Glargine Intervention)

ORIGIN

A Multicenter, International Randomized, 2x2 Factorial Design Study to Evaluate the Effects of Lantus (Insulin Glargine) Versus Standard Care, and of Omega-3 Fatty Acids Versus Placebo, in Reducing Cardiovascular Morbidity and Mortality in High Risk People With Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT) or Early Type 2 Diabetes Mellitus: The ORIGIN Trial (Outcome Reduction With Initial Glargine Intervention)

Sanofi ClinicalTrials.gov

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2 other identifiers

LTS6035HOE901/4032

Study Type

interventional

Target

12,537

Locations

37 countries

Sites

Timeline

RegisteredOct 2003

StartedAug 2003

CompletionDec 2011

Brief Summary

The primary objectives of the ORIGIN study were:

To determine whether insulin glargine-mediated normoglycemia can reduce cardiovascular morbidity and/or mortality in people at high risk for vascular disease with either Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT) or early type 2 diabetes;
To determine whether omega-3 fatty acids can reduce cardiovascular mortality in people with IFG, IGT or early type 2 diabetes. The secondary objectives of the insulin glargine study were to determine if insulin glargine-mediated normoglycemia can reduce:
total mortality (all causes);
the risk of diabetic microvascular outcomes;
the rate of progression of IGT or IFG to type 2 diabetes.

Trial Health

On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment

12,537

participants targeted

Target at P75+ for phase_3

Timeline

Completed

Started Aug 2003

Longer than P75 for phase_3

Geographic Reach

37 countries

37 active sites

Status

completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

8.3 years study duration

Study Start

First participant enrolled

August 1, 2003

Completed

2 months until next milestone

First Submitted

Initial submission to the registry

October 1, 2003

Completed

5 days until next milestone

First Posted

Study publicly available on registry

October 6, 2003

Completed

8.2 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

December 1, 2011

Completed

Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

December 1, 2011

Completed

1.2 years until next milestone

Results Posted

Study results publicly available

January 25, 2013

Completed

Last Updated

January 31, 2013

Status Verified

January 1, 2013

Enrollment Period

8.3 years

First QC Date

October 1, 2003

Results QC Date

December 18, 2012

Last Update Submit

January 24, 2013

Conditions

Diabetes Mellitus, Non-Insulin-Dependent

Keywords

Impaired Fasting Glucose (IFG)Impaired Glucose Tolerance (IGT)

Outcome Measures

Primary Outcomes (2)

Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI) or Nonfatal Stroke
Number of participants with a first occurrence of one of the above events. The outcome's evaluation is based on the number of such positively-adjudicated first events occurring for patients assigned to the study groups. Assessments of the above events were reviewed by the Event Adjudication Committee who was kept blinded to the group assignment of participants. Statistical analysis is performed on the time from randomization to the first occurrence of the events. Number of participants with a composite endpoint (i.e. with first occurrence of CV death, nonfatal MI or nonfatal stroke) is provided in the first row of the statistical table.
from randomization until study cut-off date (median duration of follow-up: 6.2 years)
Composite of the First Occurrence of Cardiovascular (CV) Death, Nonfatal Myocardial Infarction (MI), Nonfatal Stroke, Revascularization Procedure or Hospitalization for Heart Failure (HF)
Number of participants with a first occurrence of one of the above events (revascularization procedures included coronary artery bypass graft, percutaneous transluminal coronary angioplasty (PTCA) i.e. balloon, PTCA with stent, other percutaneous intervention, carotid angioplasty with/without stent, carotid endarterectomy, peripheral angioplasty with or without stent, peripheral vascular surgery, and limb amputation due to vascular disease). The outcome's evaluation is based on the number of such positively-adjudicated first events occurring for patients assigned to the study groups. Assessments of the above events were reviewed by the Event Adjudication Committee who was kept blinded to the group assignment of participants. Statistical analysis is performed on the time from randomization to the first occurrence of the events. Number of participants with a composite endpoint (i.e. with first occurrence of the events) is provided in the first row of the statistical table.
from randomization until study cut-off date (median duration of follow-up: 6.2 years)

Secondary Outcomes (3)

Total Mortality (All Causes)
from randomization until study cut-off date (median duration of follow-up: 6.2 years)
Composite Diabetic Microvascular Outcome (Kidney or Eye Disease)
from randomization until study cut-off date (median duration of follow-up: 6.2 years)
Incidence of Development of Type 2 Diabetes Mellitus in Participants With IGT and/or IFG
from randomization until the last follow-up visit or last OGTT (median duration of follow-up: 6.2 years)

Other Outcomes (2)

Number of Patients With Various Types of Symptomatic Hypoglycemia Events
on-treatment period (median duration of follow-up: 6.2 years)
Number of Patients With First Occurrence of Any Type of Cancer
from randomization until study cut-off date (median duration of follow-up: 6.2 years)

Study Arms (4)

Insulin glargine + omega-3 polyunsaturated fatty acids

EXPERIMENTAL

* Insulin glargine once daily by subcutaneous injection in a titrated regimen targeting a fasting plasma glucose (FPG) level of ≤95 mg/dL (5.3 mmol/L) * One capsule of omega-3 polyunsaturated fatty acids once daily

Drug: insulin glargine (HOE901)Drug: omega-3 polyunsaturated fatty acids (PUFA)Device: reusable pen device for insulin injection

Insulin glargine + placebo

EXPERIMENTAL

* Insulin glargine once daily by subcutaneous injection in a titrated regimen targeting a fasting plasma glucose (FPG) level of ≤95 mg/dL (5.3 mmol/L) * One capsule of placebo once daily

Drug: insulin glargine (HOE901)Drug: placeboDevice: reusable pen device for insulin injection

Standard care + omega-3 polyunsaturated fatty acids

EXPERIMENTAL

• One capsule of omega-3 polyunsaturated fatty acids once daily

Drug: omega-3 polyunsaturated fatty acids (PUFA)

Standard care + placebo

PLACEBO COMPARATOR

• One capsule of placebo once daily

Drug: placebo

Interventions

insulin glargine (HOE901)DRUG

Cartridges for use in a pen device, each containing 3 mL of insulin glargine 100 U/mL solution for injection

Also known as: Lantus®

Insulin glargine + omega-3 polyunsaturated fatty acidsInsulin glargine + placebo

omega-3 polyunsaturated fatty acids (PUFA)DRUG

Gelatin capsules (containing icosapent ethyl esters 465 mg and doconexent ethyl esters 375 mg) for oral administration

Also known as: Omacor®

Insulin glargine + omega-3 polyunsaturated fatty acidsStandard care + omega-3 polyunsaturated fatty acids

placeboDRUG

Matching placebo gelatin capsules (containing olive oil) for oral administration

Insulin glargine + placeboStandard care + placebo

reusable pen device for insulin injectionDEVICE

Also known as: OptiPen® Pro 1

Insulin glargine + omega-3 polyunsaturated fatty acidsInsulin glargine + placebo

Eligibility Criteria

Age50 Years+

Sexall

Healthy VolunteersNo

Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

I1. Individuals with IFG and/or IGT, or early diabetes, as defined below.
Glucose tolerance status was determined by a 75 g oral glucose tolerance test (OGTT) that was performed fasting (ie, no consumption of food or beverage other than water for at least 8 hours) at the time of screening for all candidates who were not known to have diabetes. The qualifying OGTT could be obtained up to 4 weeks prior to screening provided that anti-diabetic therapy (if any) remained unchanged between the qualifying OGTT and the screening visit. Two plasma glucose values were drawn during the OGTT - a fasting value (FPG) and a value drawn two hours after the 75 g oral glucose load was administered (postprandial plasma glucose \[PPG\]).
\- Impaired glucose tolerance (IGT), defined as a PPG value ≥140 and \<200 mg/dL (ie, ≥7.8 and \<11.1 mmol/L), with a FPG \<126 mg/dL (7.0 mmol/L).
\- Impaired fasting glucose (IFG), defined as an FPG ≥110 and \<126 mg/dL (≥6.1 and \<7 mmol/L), without diabetes mellitus (PPG must be \<200 mg/dL \[11.1 mmol/L\]).
\- Early type 2 diabetes, defined as a FPG ≥126 mg/dL (7.0 mmol/L) or a PPG of ≥200 mg/dL (11.1 mmol/L), or a previous diagnosis of diabetes, and either:
on no pharmacological treatment (while ambulatory) for at least 10 weeks prior to screening, with screening glycated hemoglobin \<150% of the upper limit of normal (ULN) for the laboratory (eg, \<9% if the ULN is 6%)
or taking one oral antidiabetic drug (OAD) from among sulfonylureas (SU), biguanides, thiazolidinediones (TZDs), alpha-glucosidase inhibitors (AGIs), and meglitinides (MGTs) at a stable dose while ambulatory for at least 10 weeks at the time of screening (or for the 10 weeks prior to hospitalization if identified while hospitalized for a CV event), with screening glycated hemoglobin \<133% of the ULN for the laboratory (eg, \<8% if the ULN is 6%) if taking this medication at half-maximum dose or greater, and glycated hemoglobin \<142% of the ULN for the laboratory (eg, \<8.5% if the ULN is 6%) if taking this medication at less than half-maximum dose. Individuals taking combination products containing two or more OADs were not eligible.
I2. Men or women aged 50 years and older
I3. At least one of the following CV risk factors:
previous myocardial infarction (MI) (≥ 5 days prior to randomization)
previous stroke (≥ 5 days prior to randomization)
previous coronary, carotid or peripheral arterial revascularization
angina with documented ischemic changes (at least 2 mm ST segment depression on electrocardiogram during a Graded Exercise Test \[GXT\]; or with a cardiac imaging study positive for ischemia); or unstable angina with documented ischemic changes (either ST segment depression of at least 1 mm or an increase in troponin above the normal range but below the range diagnostic for acute myocardial infarction)
microalbuminuria or clinical albuminuria (an albumin: creatinine ratio ≥ 30 μg/mg in at least one or timed collection of urine with albumin excretion ≥20 μg/min or ≥30 mg/24 hours or total protein excretion ≥500 mg/24 hours)
left ventricular hypertrophy by electrocardiogram or echocardiogram
+7 more criteria

You may not qualify if:

E1. Type 1 diabetes.
E2. Requiring ambulatory insulin treatment or uncontrolled or symptomatic hyperglycemia that is likely to require the addition of ambulatory insulin therapy or a new antidiabetic agent either before or within 2 weeks after randomization.
E3. Known anti-glutamic acid decarboxylase antibody (anti-GAD Ab) positivity in the past.
E4. Screening glycated hemoglobin ≥150% of the ULN for the laboratory (eg, ≥9% if the ULN is 6%).
E5. Unwillingness to inject insulin or perform self-monitoring of blood glucose.
E6. Nonadherence to the run-in requirement to inject placebo insulin and do capillary glucose monitoring for at least 4 days prior to randomization.
E7. Coronary artery bypass grafting (CABG) either planned at the time of screening, or CABG within the 4 years prior to screening - however, participants with angina, MI, or stroke since a previous CABG will be eligible for randomization, even if the last CABG was within 4 years.
E8. Serum creatinine \>2.0 mg/dL (176 μmol/L) at screening.
E9. Active liver disease, or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>2.5 times ULN at screening.
E10. Chronic or recurrent treatment with systemic corticosteroids, or niacin treatment for hyperlipidemia.
E11. Heart failure of New York Heart Association (NYHA) Functional Class III or IV.
E12. Expected survival of \<3 years for non-CV causes such as cancer.
E13. Any other factor likely to limit protocol compliance or reporting of adverse events (AEs).
E14. Unwilling or unable to discontinue TZDs.
E15. Simultaneous participation in any other clinical trial of an active pharmacologic agent.
+5 more criteria

Contact the study team to confirm eligibility.